Quaternary ammonium compounds

ABSTRACT

Quaternary ammonium carbamate, thiocarbamate, dithiocarbamate and carbamide compounds. Typical examples are (C4H9NHCOO(CH2)2N (CH3)2C12H25)Br (C4H9NHCSO(CH2)2N (CH3)2C12H25)Br (CH3NHCSS(CH2)2N (CH3)2C12H25)Br (C2H5NHCONH(CH2)2N (CH3)2C12H25)Br These compounds are effective against gram positive bacteria and fungi and reduce caries and inhibit formation of oral calculus. The thiocarbamates can be prepared by converting amino alcohols to sodium salts thereof with metallic sodium and reacting isothiocyanates with the sodium salts followed by quaternization. The carbamates can be prepared by reacting isocyanates with amino alcohols followed by quaternization. The dithiocarbamates can be prepared by reacting isothiocyanates with sodium salts of aminoalkanethiols followed by quaternization. The carbimides can be prepared by reacting isocyanates with alkanediamines followed by quaternization.

United States Patent Robert Andrew Bauman New Brunswick, NJ.

Mar. 14, 1968 Nov. 16, 1971 Colgate-Palmolive Company New York, NY.

Continuation-impart of application Ser. No. 578,981, Sept. 13, 1966, now abandoned. This application Mar. 14, 1968, Ser. No. 712,968

Inventor Appl. No. Filed Patented Assignee QUATERNARY AMMONIUM COMPOUNDS 10 Claims, No Drawings Int.

Primary Examiner- Lewis Gotts Assistant Examiner-G. Hollrah Anomeyr-Herbert S. Sylvester, Ronald S. Cornell, Norman Blumenkopf, Thomas .I. Corum, Richard N. Miller and Robert L. Stone ABSTRACT: Quaternary ammonium carbamate, thiocarbamate, dithiocarbamate and carbamide compounds. Typical examples are These compounds are effective against gram positive bacteria and fungi and reduce caries and inhibit formation of oral calculus. The thiocarbamates can be prepared by converting amino alcohols to sodium salts thereof with metallic sodium and reacting isothiocyanates with the sodium salts followed by quatemization. The carbamates can be prepared by reacting isocyanates with amino alcohols followed by quaternization. The dithiocarbamates can be prepared by reacting isothiocyanates with sodium salts of aminoalkanethiols followed by quatemization. The carbimides can be prepared by reacting isocyanates with alkanediamines followed by quatemization.

QUATERNARY AMMONIUM COMPOUNDS This application is a continuation-in-part of Ser. No. 57 8,981, filed Sept. 13, 1966, now abandoned.

The present invention relates to novel quaternary ammonium compounds and, more particularly, to quaternary am- 5 monium compounds containing a carbamate, or a thiocarbamate, or a dithiocarbamate, or a carbamide group. The novel quaternary ammonium compounds of the present invention are useful in reducing caries, inhibiting acid formation in the oral cavity, in inhibiting formation of oral calculus, and/or as effective fungicides.

Novel compounds of the invention are superior to quatemary ammonium compounds, to carbamates and to thiocarbamates previously known to have some efficacy in in vitro anticaries tests. They also reduce caries and inhibit formation in vivo in mammals.

It has been discovered that quaternary ammonium compounds having a carbamate, or a thiocarbamate, or a dithiocarbarnate, or a carbamide group have greatest usefulness as bactericides against gram-positive organisms and as fungicides and as effective anticaries and calculus inhibiting agents. The compounds of the present invention can be represented by the following formula:

wherein R is selected from the group consisting of an alkyl group containing one to 22 carbon atoms, an aryl group, an aryl group substituted by halogen, i.e., Cl Br, F, I, an aryl group substituted by alkyl containing one to five carbon atoms, and an aryl group substituted by alkoxy containing one to five carbon atoms;

R" and R'" are each selected from the group consisting of acyclic aliphatic hydrocarbon radicals having one to two carbon atoms and hydrocarbon radicals that form a ring system including the (CH,),,N group and R" and R';

R"" is an alkyl group containing one to 22 carbon atoms, an aryl group substituted by halogen, i.e., Cl, Br, F, 1; an aryl group substituted by alkyl containing one to five carbon atoms; an aryl group substituted by alkoxy group containing one to five carbon atoms, divalent aliphatic groups having up to 10 carbon atoms, divalent aryl groups, monovalent aryl group;

Y is selected from the group consisting of oxygen and sulfur;

Z is selected from the group consisting of oxygen, NH and sulfur;

X is a compatible anion such as Cl', Br, F' 80 M6 and n is an integer 2 to 6.

When the (CH,),,NR"R"'-groups form a ring system,

typically the ring system is quinuclidine or piperidine,

may be C11,, or both may be C,l-l,, or one may be Cl-l,and the other (3H,.

[t is to be observed that the compounds generally described by the foregoing formula are effective against gram-positive organisms such as Staph. aureus, Str. mitis 8-3, Bacillus subtilis, Corynebacterium acnes, and against fungi, such as Candida albicans and Tnchophytan memagrophytes. Of the compounds represented by the general formula given hereinbefore, those compounds in which either R or R"" is a longchain alkyl group (l0-l6carbon atoms) and the other of R and R"" is a short-chain alkyl (one to four carbon atoms) or aryl, or aralkyl group containing one to five carbon atoms in the alkyl moiety are particularly effective against gram-positive organisms. Of the compounds represented by the general formula provided hereinbefore, the compounds particularly effective against fungi are those in which R is an aromatic group and particularly an aryl group or an aryl group substituted by halogen, and R"" is a long-chain alkyl group (10 to 18 carbon atoms).

The compounds of the invention which are most effective in reducing caries and inhibiting formation of oral calculus are those in which R"" is along alkyl chain having 10 to 16 carbon atoms. The compounds of the general formula given herein which are most effective in in vitro anticaries are those in which one of R or R"" is a long alkyl chain of 10 to 14 carbon atoms and the other of R or R"" is an aryl group or a halogen-substituted aryl group or short alkyl chain of one to four carbon atoms and n is the range of 2 to 6.

The thiocarbamate compounds can be prepared by converting the amino alcohol to the sodium salt thereof with metallic sodium in any suitable manner. An isothiocyanate is reacted with the aforesaid sodium salt. The reaction product is isolated in any suitable manner and quatemized with an alkylhalide or aralkyl halide.

The carbamate compounds can be prepared by reacting an isocyanate with the aminoalcohol, followed by quatemization with an alkyl or aralkyl halide.

The dithiocarbarnate compounds can be prepared by reacting an isothiocyanate with the sodium salt of the aminoalkanethiol followed by quatemization with an alkyl or aralkyl halide.

The carbamide compounds can be prepared by reacting an isocyanate with the alkanediamine followed by quatemization with an alkyl or aralkyl halide.

The following examples illustrate the manner in which compounds of the invention are prepared.

Example 1 2-hydroxyethyl dimethyldodecylammonium bromide, N-butylthiocarbamate is prepared in the following manner: Sodium (0.095 gr. atom) was powdered under 100 milliliters of xylene. 2-dimethylaminoethanol (0.095 mole) was added during 10 minutes and the mixture stirred until the sodium dissolved. Normal butyl isothiocyanate (0.10 mole) was added at room temperature (about 75 F.). After standing at ambient 7 temperature (about 75 F.) for about minutes the reaction mixture was poured into about 500 milliliters of water and the resultant slurry neutralized with 16 milliliters of concentrated hydrochloric acid. After removing the xylene, the aqueous layer was washed with diethyl ether and then made basic with sodium hydroxide. The oil is extracted with ether and recovered by evaporation or distillation of the ether. The residue, i.e., the product, O-(Z-dimethylaminoethyl) N-butylthiocarbamate has a neutral equivalent of 205 (theory 204.3). A portion of the amine so obtained (0.01 mole) was mixed with 0.01 mole of l-bromododecane and kept at ambient (room temperature 75 F.) for 2 weeks. The resultant crystalline mass was triturated with diethyl ether leaving 4.l grams of product which was recrystallized from 30 milliliters of ethyl acetate, i.e., about seven times as much ethyl acetate as product by weight. The recovered crystals weighed 3.6 grams and had a melting point of 91 to 93 C.

Analysis for C l'MErN OS Calculated Found 55.6l% Carbon 55.07% [0.00% Hydrogen l0.0l% 6.18% Nitrogen 6.04%

The infrared and nuclear magnetic resonance spectra agree with the following structural formula:

The thiocarbamate compounds for which structural formulas are given in the table below have been similarly prepared. All aromatic substitution is para. Thus,

(compound 23 in the table below) is prepared using ethyl isothiocyanate in place of normal butyl isothiocyanate.

Example 2 Z-hydroxyethyldirnethyldodecylammonium bromide, N-butylcarbamate is prepared in the following manner. A solution of 58 g. (0.65 mole) Z-dimethylaminoethanol in 150 ml. ether was treated over a period of 1.5 hours with 70 g. (0.7] mole) n-butyl isocyanate. After stirring another 2 hours the reaction mixture was stripped of ether and distilled in vacuum. The product, Z-dimethylaminoethyl N-butylcarbamate was collected at l06ll .2 Torr. For quaternization 75 g. (0.40 mole) of the above prepared amine was combined with 105 g. (0.42 mole) l-bromododecane and allowed to stand stoppered for 9 days. At this time the reaction mixture was a stiff gel with some crystalline portions. By solution in ethyl acetate (900 ml.) and chilling, 160 g. of product was obtained in crystalline form. After two more recrystallizations from ethyl acetate, the material melted at 64 C. to liquid crystals and to a liquid at l 1 C.

Analysis for C l-l lirN O Calculated Found 57.65 Carbon 57.87 l0.J7 Hydrogen 10.82

The infrared and nuclear magnetic resonance spectra agree with the following structural formula:

The carbamate compounds for which structural formulas are given in the table below have been similarly prepared. All aromatic substitution is para.

Example 3 Z-(Methyldithiocarbamyl) ethyldimethyldodecylarnmonium bromide was prepared as follows. A solution of 15.0 g. (0.105 mole) of Z-dimethylaminoethanethiol hydrochloride in ml. of water was neutralized with 210 ml. of IN sodium hydroxide solution and then treated immediately with 8.1 g. (0.1 1 mole) of methyl isothiocyanate dissolved in a few ml. of methanol. Following 30 minutes of stirring at room temperature, the reaction mixture was treated with 105 ml. of IN hydrochloric acid. Afiter 1 hour the precipitated solid was removed by filtration, dried, and recrystallized rom benzene- Slcellysolve B. The yield was 9.7 (54 percent), mp. 1 10 l l2.

A solution of 3.0 g. (0.017 mole) of the above-prepared 2- dimethylaminoethyl methyldithiocarbamate and 4.2 g. (0.017 mole) of l-bromododecane in 25 ml. acetone was prepared and set aside for 2 weeks. The solid mass which had formed was recrystallized from anhydrous 3A alcohol, to recover 4.3 g. mp. l74-l75.

Analysis for C l'i lfirN s Calculated Found 50.56 Carbon 5|.3l 9J9 Hydrogen 9.30 6.55 Nitrogen 6.54

The infrared and nuclear magnetic resonance spectra agree with the following structural formula:

Example 4 2-( Ethylureido )ethyldimethyldodecylammonium bromide was prepared as follows. Five grams (0.057 mole) of N,N- dimethylethylenediamine dissolved in 10 ml. of ether was treated dropwise with 4.3 g. (0.06 mole) of ethyl isocyanate dissolved in 10 ml. of ether. After 15 minutes the reaction mixture was diluted with more ether and saturated with hydrogen chloride gas. The precipitate was triturated with acetone and dried. in titrating with sodium chloride two end points were observed indicating it was the dihydrochloride of l-ethyl-3-(2-dimethylaminoethyl)urea. By neutralization with sodium hydroxide, evaporation, extraction with ether, and evaporation 5.5 g. of free base was obtained. l.6 g. (0.01 mole) of the above prepared amine and 2.5 g. (0.0l mole) l bromododecane were dissolved in 25 ml. acetone and allowed to stand overnight. The mixture was then refluxed for 3 hours. Evaporation of the solvent left a mixture of product and starting materials which was separated by other extraction, the product being insoluble. The 1.6 g. material so obtained was recrystallized from ethyl acetate, m.p. 93.5-95.3.

Analysis for C ll-l lBrNJl Calculated Found 55.86 Carbon 55.78 10.37 Hydrogen 10.95 10.29 Nitrogen 10.20

The infrared and nuclear magnetic resonance spectra agree with the following structural formula:

The following table lists additional compounds of the invention:

TABLE Melting oint, egress No. Compound centigrade when submitted to a series of tests to determine their ability to prevent aeid formation in incubated saliva both as is and/or as adsorbed upon protein and/or their ability to prevent growth of Streptococcus sp. HS-6 in a halo test, the compounds which are highly efiective are numbers 1-4, 6, 16, 21-24, 27, 30, 31, and 33-44 of the above list of compounds of the general formula. The tests set forth in Examples 5 and 6 below evidence the efl'ectiveness of the compounds of the invention in reducing caries and inhibiting formation of calcu- 10 lus.

Example 5 The following test was conducted with compounds 2, 23, and of the above list of compountk to determine their ability to reduce caries in animals. Caries-susceptible hamsters bred either from the Keyes strain or the NIDR (National Institute for Dental Research) strain in groups of 15 males and 15 females per control group and per each test group were fed ad lib. a Mitchell cariogenic diet and received constant deionized water. Each day each hamsters teeth were swabbed 30 seconds by cotton-tipped swabs, the control group with water and each test group with its test solution. Afier 6 weeks of swabbing the animals were sacrificed, and the defleshed heads were scored by a modified version of the Keyes scoring method. Mean averages and percentage changes from the .control were determined and tested statistically to determine the significance.

The resultsset forth above indicated the significant effectiveness of the quaternary compounds of the invention in reducing caries formation.

Example 6 To show the effectiveness of compounds 2 and 23 in inhibiting the development of dental calculus, litter-mated Sprague- Dawley rats, 60 days old, in groups of 15 males and 15 females were fed a Zipkin-McClure calculus diet. For 2 to 3 weeks the teeth of each animal were swabbed for 30 seconds each day with a test solution or water for the control group. The animals 1 were then sacrificed, defleshed and scored by Baer's method for calculus. The results were analyzed by Student's t" test and in the results quoted were 99 percent significant.

. concenmfion Caries Reduction Compound Test Solution Males Females The results set forth above indicated that significant effectiveness of the quaternary compounds of the invention-in inhibiting formation of oral calculus.

When compounds of the instant invention are intended for use in compositions which reduce formation of caries and in- 70 hibit formation of oral calculus, they are typically incorporated in oral preparations in effective amounts up to about 5 percent by weight, preferably 0. l-l percent and most preferably 0.25-0.5 percent by weight of the oral preparation.

Typically, the oral preparation is a dentifrice, such as a dental cream, tablet or power, containing as a vehicle about 20-95 percent by weight of a water-insoluble polishing material, preferably including water-insoluble phosphate such as dicalcium phosphate, tricalcium phosphate, trimagnesium phosphate. The dentifrice may also include water, binders such as glycerine, sorbitol, propylene glycol, and polyethylene glycol 400; detergents; gelling agents such as Irish moss and sodium carboxymethyl cellulose; additional antibacterial agents; coloring or whitening agents; preservative; silicones; chlorophyll compounds; additional ammoniated materials; flavoring or sweetening materials; and compounds which provide fluorine-containing ion such as sodium fluoride, stannous fluoride and sodium monofluorophosphate.

The oral preparation may also be a liquid such as mouth rinse which typically contains 20-99 percent by weight of an aqueous alcohol vehicle, the alcohol being a cosmetically acceptable and nontoxic alcohol such as ethanol or isopropyl alcohol and being present in amount of about -30 percent by weight of the oral preparation.

Such oral preparations are typically applied by brushing the teeth or rinsing the oral cavity for 30 to 90 seconds at least once daily. Typical oral preparations of the invention which can be applied in this manner are set forth below.

The antimicrobial effectiveness of the compounds of the invention was evidenced in the test set forth in Examples 9 and 10, below.

Example 9 To illustrate the antibacterial character of compounds of the instant invention the following halo test was performed. The cariogenic strain of streptococcus (HS6) obtained from NIDIR was grown in fluid thioglycollate medium at 37 C. for 24 hours. A 2 percent inoculum was added to fluid thiolycollate agar at 45 C. After thorough mixing it was dispersed in 20 ml. aliquots into sterile petri dishes. A %-inch diameter sterile paper disc was saturated with a solution of the test compound and placed in firm contact with this agar. Then 20 ml. of uninoculated fluid thioglycollate agar was poured into the petri dishes to reduce the oxygen tension. The dishes were incubated for 24 hours at 37 C. The results which are averages of duplicate determinations are reported as mm. of inhibition of bacterial growth around the disc.

Halo Test Results Compound Halo, mm. Compound Halo. mm.

l 20 23 35 3 28 M M 4 29 27 27 6 21 29 27 7 26 30 36 8 36 3 l 34 9 '27 33 20 l l 28 M 30 l 2 36 36 33 l 3 3 I 38 3 l l 4 5 l 39 27 l 5 as 410 2'7 2 2 43 4 l 15 These halo tests evidenced antigram-positive bacterial effectiveness of compounds of the invention.

Example 10 The antimicrobial nature of the compounds was shown by a standard test tube serial dilution test in which an appropriate number of test tubes of broth containing decreasing concentrations of the test agent was inoculated with the test organism. After a suitable period of incubation the tubes were examined for the presence or absence of growth. The activity of the test agent was the lowest concentration which inhibited the growth of the organism and is expressed as the minimal inhibitory concentration (M.l.C.) in g /ml.

RESULTS (M.I.C.)

S. S. mitis C. C. mentgroaureus (8-3) subtilw ac'nes albicans pin tea These dilution tests evidence the eflectiveness of compounds of the invention against gram-positive bacteria and fungi.

When used against bacteria or fungi, compounds of the instant invention may be applied directly to the surface to be protected or may be dissolved in a pharmaceutical carrier. Typically, an efl't'ective amount, e.g. 0.1 percent to about 10 percent by weight of the compound, is included in an inert carrier and a dispersing or surface-active agent. Alternatively, an effective amount, e.g. 0.1 percent to about 10 percent by weight, may be incorporated into a solid carrier which may be inert, such as talc, clay, diatomaceous earth, flour, etc.

Although this invention has been described with reference to specific examples, it will be apparent to one skilled in the art that various modifications may be made thereto which fall within its scope.

I claim:

1. A chemical compound having a composition represented by the fonnula where R is selected from the group consisting of an alkyl group containing one to 22 carbon atoms, a phenyl group and a phenyl group substituted by halogen selected from the group consisting of chlorine and bromine; R" and R' are each selected from the group consisting of an alkyl group containing one to two carbon atoms R"" is an alkyl group containing to 22 carbon atoms, a phenyl group substituted by halogen selected from the group consisting of chlorine and bromine, divalent alkyl group having up to 10 carbon atoms, divalent phenyl group and monovalent phenyl group;

Y is selected from the group consisting of oxygen and sulfur;

Z is selected from the group consisting of oxygen and sulfur,

at least one of Y and 2 being sulfur; n is an integer 2 to 6; and

X is a compatible anion selected from the group consisting of chloride, bromide, iodide and methosulfate. 2. A chemical compound as claimed in claim 1 wherein said composition is represented by the formula:

and in which R" and R' are each selected from the group consisting of alkyl radicals having one to two carbon atoms.

3. A chemical compound as set forth in claim 2 wherein n is 2.

4. A chemical compound having a composition represented by the formula:

R"" is an alkyl group containing 16 to 22 carbon atoms, a phenyl group substituted by halogen selected from the group consisting of chlorine and bromine, divalent alkyl group having up to 10 carbon atoms, divalent phenyl oup and monovalent phenyl group;

n is an integer 2 to 6; and

X is a compatible anion selected from the group consisting of chloride, bromide, iodide and methosulfate.

5. A chemical compound as set forth in claim 4 wherein one of R and R"" is a long-chain alkyl group having 10 to 18 carbon atoms.

6. A chemical compound as set forth in claim 5 wherein R is selected from the group consisting of CJ-l, and ClCJ'l and R" is selected from the group consisting of C ll and C15?!- 7. A chemical compound as set forth in claim 4 wherein R is selected from the goup consisting of phenyl and halogensubstituted phenyl and R"" is a long-chain alkyl group having 10 to 18 carbon atoms.

8. A chemical compound as set forth in claim 4 wherein R"" is an alkyl group selected form the group consisting of C l-l C li and C ll and R is selected from the group consisting of CH CgHg, C,H Cg; and ClC,l-i

9. A chemical compound as claimed in claim 4 wherein R is an alkyl goup containing one to 22 carbon atoms and R"" is a long alkyl chain having 10 to 14 carbon atoms and n is in the range of 2 to 6.

10. A chemical compound as claimed in claim 4 wherein said composition is represented by the formula:

# i i i i 

2. A chemical compound as claimed in claim 1 wherein said composition is represented by the formula: and in which R'''' and R'''''' are each selected from the group consisting of alkyl radicals having one to two carbon atoms.
 3. A chemical compound as set forth in claim 2 wherein n is
 2. 4. A chemical compound having a composition represented by the formula: where R'' is selected from the group consisting of an alkyl group containing one to 22 carbon atoms, a phenyl group and a phenyl group substituted by halogen selected from the group consisting of chlorine and bromine; R'''' and R'''''' are each an alkyl group containing one to two carbon atoms; R'''''''' is an alkyl group containing 16 to 22 carbon atoms, a phenyl group substituted by halogen selected from the group consisting of chlorine and bromine, divalent alkyl group having up to 10 carbon atoms, divalent phenyl group and monovalent phenyl group; n is an integer 2 to 6; and X is a compatible anion selected from the group consisting of chloride, bromide, iodide and methosulfate.
 5. A chemical compound as set forth in claim 4 wherein one of R'' and R'''''''' is a long-chain alkyl group having 10 to 18 carbon atoms.
 6. A chemical compound as set forth in claim 5 wherein R'' is selected from the group consisting of C6H5 and C1C6H4 and R'''''''' is selected from the group consisting of C12H25 and C18H37.
 7. A chemical cOmpound as set forth in claim 4 wherein R'' is selected from the group consisting of phenyl and halogen-substituted phenyl and R'''''''' is a long-chain alkyl group having 10 to 18 carbon atoms.
 8. A chemical compound as set forth in claim 4 wherein R'''''''' is an alkyl group selected from the group consisting of C10H21, C12H25 and C14H29 and R'' is selected from the group consisting of CH3, C2H5, C4H9, C6H5 and ClC6H4.
 9. A chemical compound as claimed in claim 4 wherein R'' is an alkyl group containing one to 22 carbon atoms and R'''''''' is a long alkyl chain having 10 to 14 carbon atoms and n is in the range of 2 to
 6. 10. A chemical compound as claimed in claim 4 wherein said composition is represented by the formula: 